Transport across, blood-brain barrier

Bradbury. M.W.B. (1985) The blood-brain barrier. Transport across the cerebral endothelium. Circulation Research, 57. 213-222. 

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

Irrespective of whether or not DA can cross the blood-brain barrier it will certainly be destroyed after oral administration by MAO and COMT in the gut and liver before achieving an adequate plasma concentration. Levodopa, by contrast, is not a good substrate for MAO, although metabolised by COMT (Fig. 15.4) and is transported across the gut and blood-brain barrier. 

Kerper LE, Ballatori N, Clarkson TW. 1992. Methylmercury transport across the blood-brain barrier by an amino acid carrier. Am J Physiol 262 R761-R765. 

Pardridge, W.M., and Connor, J.D. Saturable transport of amphetamines across the blood-brain barrier. Experientia 29 302-304, 1973. 

FIGURE 29-2. Levodopa absorption and metabolism. Levodopa is absorbed in the small intestine and is distributed into the plasma and brain compartments by an active transport mechanism. Levodopa is metabolized by dopa decarboxylase, monoamine oxidase, and catechol-O-methyltransferase. Carbidopa does not cross the blood-brain barrier. Large, neutral amino acids in food compete with levodopa for intestinal absorption (transport across gut endothelium to plasma). They also compete for transport across the brain (plasma compartment to brain compartment). Food and anticholinergics delay gastric emptying resulting in levodopa degradation in the stomach and a decreased amount of levodopa absorbed. If the interaction becomes a problem, administer levodopa 30 minutes before or 60 minutes after meals. 

Levodopa, a dopamine precursor, is the most effective agent for PD. Patients experience a 40% to 50% improvement in motor function. It is absorbed in the small intestine and peaks in the plasma in 30 to 120 minutes. A stomach with excess acid, food, or anticholinergic medications will delay gastric emptying time and decrease the amount of levodopa absorbed. Antacids decrease stomach acidity and improve levodopa absorption. Levodopa requires active transport by a large, neutral amino acid transporter protein from the small intestine into the plasma and from the plasma across the blood-brain barrier into the brain (Fig. 29-2). Levodopa competes with other amino acids, such as those contained in food, for this transport mechanism. Thus, in advanced disease, adjusting the timing of protein-rich meals in relationship to levodopa doses may be helpful. Levodopa also binds to iron supplements and administration of these should be spaced by at least 2 hours from the levodopa dose.1,8,16,25... 

Gao, B., et al. Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. J. Pharmacol. Exp. Ther. 2000, 294, 73-79. 

Tamai I, Tsuji A. Transporter-mediated permeation of drugs across the blood-brain barrier. J Pharm Sci 2000 89(11) 1371 1388. 

The exit of drugs from the CNS can involve (1) diffusion across the blood-brain barrier in the reverse direction at rates determined by the lipid solubility and degree of ionization of the drug, (2) drainage from the cerebrospinal fluid (CSP) into the dural blood sinuses by flowing through the wide channels of the arachnoid villi, and (2) active transport of certain organic anions and cations from the CSF to blood across the choroid plexuses... 

Defective transport of glucose across the blood-brain barrier is caused by deficiency in the glucose transporter protein 703... 

De Vivo, D. C., Trifiletti, R. R., Jacobson, R. I., Ronen, G. M., Behmand, R. A. and Harik, S. I. Defective glucose transport across the blood-brain barrier as a cause of persistent hypo-glycorrhachia, seizures, and developmental delay. N. Engl. J. Med. 325 703-709,1991. 

A microdialysis study was carried out to examine transport of oxycodone into the brain of rats [67], Oxycodone was administered by i.v. infusion, and unbound drug concentrations were monitored in both vena jugularis and striatum. Steady-state equilibrium was reached rapidly and drug levels in the two compartments declined in parallel at the end of the infusion. An unbound brain to unbound plasma ratio of 3.0 was measured which is 3- to 10-fold higher than for other opioids, and explains the similar in vivo potency of oxycodone in spite of lower receptor affinity. The authors interpret these data as de facto evidence of the existence of an as-yet unidentified transporter that carries oxycodone across the blood-brain barrier. 

Leptin signalling is via monomeric receptors in the brain. A short-form of the leptin receptor (Lep-R) is required to transport the hormone across the blood-brain barrier and a long-form Lep-R is located in the hypothalamus. The long-form is functionally linked with a particular type of receptor-associated tyrosine kinase called Janus kinase (JAK, see Section 4.7) whose function is to phosphorylate a STAT (signal transducer and activator of transcription) protein a similar mechanism to that often associated with signalling by inflammatory cytokines. 

T. Kageyama, M. Nakamura, A. Matsuo, Y. Yamasaki, Y. Takakura, M. Hashida, Y. Kanai, M. Naito, T. Tsuruo, N. Minato, and S. Shimohama. The 4F2hc/LATl complex transports L-DOPA across the blood-brain barrier. Brain Res. 879 115— 121 (2000). 

Freshly isolated or subcultured brain microvascular endothelial cells offer a notable in vitro tool to study drug transport across the blood-brain barrier. Cells can be grown to monolayers on culture plates or permeable membrane supports. The cells retain the major characteristics of brain endothelial cells in vivo, such as the morphology, specific biochemical markers of the blood-brain barrier, and the intercellular tight junctional network. Examples of these markers are y-glutamyl transpeptidase, alkaline phosphatase, von-Willebrandt factor-related antigen, and ZO-1 tight junctional protein. The methods of... 

Van Bree JB, de Boer AG Danhof M, Breimer DD (1992) Drug transport across the blood-brain barrier. I. Anatomical and physiological aspects. Pharm Weekblad SciEd 14 305-310... 

Abbott NJ, Romero IA (1996) Transporting therapeutics across the blood-brain barrier. Mol Med Today 3 103-113... 

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